Clinton B. Wright

Early continuous ST segment monitoring in unstable angina: prognostic value additional to the clinical characteristics and the admission electrocardiogram.

BACKGROUND AND OBJECTIVE: In unstable angina, clinical characteristics, resting electrocardiography, and early continuous ST segment monitoring have been individually reported to identify subgroups at increased risk of adverse outcome. It is not known, however, whether continuous ST monitoring provides additional prognostic information in such a setting. DESIGN: Observational study of 212 patients with unstable angina without evidence of acute myocardial infarction admitted to district general hospitals, who had participated in a randomised study comparing heparin and aspirin treatment versus aspirin alone. METHODS: Clinical variables and a 12 lead electrocardiogram (ECG) were recorded at admission, and treatment was standardised to include aspirin, atenolol, diltiazem, and intravenous glyceryl trinitrate, in addition to intravenous heparin (randomised treatment). Continuous ST segment monitoring was performed for 48 h and all inhospital adverse events were recorded. RESULTS: The admission ECG was normal in 61 patients (29%), showed ST depression in 59 (28%) (17 > or = 0.1 mV), and T wave changes in a further 69 (33%). The remaining 23 had Q waves (18), right bundle branch block (four), or ST elevation (one). During 8963 h of continuous ST segment monitoring (mean 42.3 h/patient), 132 episodes of transient myocardial ischaemia (104 silent) were recorded in 32 patients (15%). Forty patients (19%) had an adverse event (cardiac deaths (n = 3), non-fatal myocardial infarction (n = 6) and, emergency revascularisation (n = 31)). Both admission ECG ST depression (P = 0.02), and transient ischaemia (P < 0.001) predicted an increased risk of non-fatal myocardial infarction or death, while no patients with a normal ECG died or had a myocardial infarction. Adverse outcome was predicted by admission ECG ST depression (regardless of severity) (odds ratio (OR) 3.41) (P < 0.001), and maintenance beta blocker treatment (OR 2.95) (P < 0.01). A normal ECG predicted a favourable outcome (OR 0.38) (P = 0.04), while T wave or other ECG changes were not predictive of outcome. Transient ischaemia was the strongest predictor of adverse prognosis (OR 4.61) (P < 0.001), retaining independent predictive value in multivariate analysis (OR 2.94) (P = 0.03), as did maintenance beta blocker treatment (OR 2.85) (P = 0.01) and admission ECG ST depression, which showed a trend towards independent predictive value (OR 2.11) (P = 0.076). CONCLUSIONS: Patients with unstable angina and a normal admission ECG have a good prognosis, while ST segment depression predicts an adverse outcome. Transient myocardial ischaemia detected by continuous ST segment monitoring in such patients receiving optimal medical treatment provides prognostic information additional to that gleaned from the clinical characteristics or the admission ECG.

Ethical Issues in Biological Psychiatric Research with Children and Adolescents

OBJECTIVEnThis article reviews, discusses, and elaborates considerations and recommendations summarized by the biological research working group at the May 1993 NIMH conference on ethical issues in mental health research on children and adolescents.nnnMETHODnNotes from the conference were summarized and supplemented by a computer search of relevant literature. Drafts were circulated for comment to national and international experts, some of whom joined as coauthors.nnnRESULTSnIssues addressed include possible overprotection by policy makers and institutional review boards arising out of the recognition of childrens special vulnerability without equal recognition of their need for research; the definition of minimal risk, which has often been equated with no risk in the case of children; assessment of the risk-benefit ratio; procedures for minimization of risk, such as improved technology, piggybacking onto clinical tests, and age-appropriate preparation; the difficulty of justifying risk for normal controls; age-graded consent; special considerations about neuroimaging; coercive inducement, both material and psychological; disposition of unexpected or unwanted knowledge about individuals, including the subjects right not to know and parents right not to tell; and socioeconomic status and cultural/ethnic equity.nnnCONCLUSIONSnThe working group adopted a position of advocacy for childrens right to research access while recognizing that this advocacy must be tempered by thoughtful protections for child and adolescent subjects.

Effects of valproic acid on β-adrenergic receptors, G-proteins, and adenylyl cyclase in rat C6 glioma cells

Valproic acid (VPA) is an anticonvulsant drug with demonstrated efficacy in the treatment of mania. In the present study, we found that chronic exposure of rat C6 glioma cells to VPA induces a coordinate decrease in multiple components of the β-adrenergic receptor- (β-AR) coupled cyclic adenosine 3′-5′monophosphate (cAMP) generating system. Chronic VPA decreased the number of β-ARs in a time- and concentration-dependent manner; the decrease of β-ARs was largely β1-AR selective and affected β-ARs in both the high- and low-affinity states. Chronic VPA also significantly attenuated receptor- and postreceptor-stimulated cAMP production, [3H]forskolin binding sites, immunolabeling of Gαs 45, and cholera toxin catalyzed ADP-ribosylation of Gαs 52 and 45. Although the precise underlying mechanisms remain to be elucidated, such profound long-term changes in the functioning of this key signaling pathway may help explain the antimanic effects of chronic VPA treatment and are worthy of further study.

Women with chest pain: is exercise testing worthwhile?

OBJECTIVE: To determine the diagnostic value of the exercise tolerance test (ETT) in women presenting with chest pain. DESIGN: Prospective study of all women presenting to a centre with chest pain between 1987 and 1993 who were assessed by an ETT and coronary angiography. SETTING: The outpatient clinic of one consultant cardiologist in a tertiary referral centre. PATIENTS: All women referred to this outpatient clinic with chest pain were screened. For inclusion, patients had to perform ETT and undergo coronary angiography. Of the 347 referred during this period, 142 were excluded because they were unable to perform ETT or because of Q waves or other abnormalities on their resting electrocardiogram. RESULTS: Overall the sensitivity of the ETT was 68% and the specificity was 61%, with a positive predictive value of 0.61 and a negative predictive value of 0.68. There were 42 false positive and 31 false negative ETT results (36% of the study group). The predictive value of a negative test was higher in younger women (< 52 years) than in the older group (> or = 52 years) (P = 0.004), but the positive predictive value in the two groups was not significantly different. The predictive value of a negative test was also higher in those with two or fewer risk factors than in those with three or more risk factors (P = 0.001). The negative predictive value for those women above 52 years with three or more risk factors (24% of the study group) was only 0.25. Lack of chest pain during ETT was associated with a higher negative predictive value in the younger group than in the older women (P = 0.006). CONCLUSIONS: In women with chest pain use of the ETT was a misleading predictor of the presence or absence of coronary disease in 36% of these patients. In particular, a negative test in older women with three or more risk factors had a very low predictive value. The inclusion of risk factors and division by age can, however, be used to identify a population at intermediate risk for coronary artery disease in whom the ETT result has the highest diagnostic utility.

Circadian variation of heart rate is affected by environment: a study of continuous electrocardiographic monitoring in members of a symphony orchestra.

Twenty four hour ambulatory ST segment monitoring was performed on 48 members (43 players and five members of the management/technical team) of the British Broadcasting Corporation (BBC) symphony orchestra without a history of cardiac disease. This period included final rehearsals and live performances (for audience and radio) of music by Richard Strauss and Mozart at the Royal Festival Hall (n = 36) and Rachmaninov and Tchaikovsky at the Barbican Arts Centre (n = 21). During the period of monitoring one person (2%) had transient ST segment changes. Mean heart rates were significantly higher during the live performances than during the rehearsals. Mean heart rates during the live performance of Rachmaninov and Tchaikovsky were significantly higher than during Strauss and Mozart in those (n = 6) who were monitored on both occasions. Mean heart rates in the management and technical team were higher than those of the players. The recognised circadian pattern of heart rate, with a peak in the morning waking hours, was altered similarly during both concert days, with a primary peak occurring in the evening hours and a lesser peak in the morning for both musicians and management/technical staff. This study showed that environmental factors are of primary importance in defining the circadian pattern of heart rate. This has important implications when identifying peak periods of cardiovascular stress and tailoring drug treatment for patients with angina pectoris.

Can C reactive protein or troponins T and I predict outcome in patients with intractable unstable angina

Objective To determine whether a single blood test for the measurement of C reactive protein, or troponin I or T concentrations could be used to stratify patients with intractable unstable angina awaiting transfer for coronary angiography by correlating these values with coronary anatomy and transient myocardial ischaemia. Design Prospective study. Setting Tertiary cardiac unit. Patients All patients admitted to their local hospital with ischaemic chest pain, uncontrolled by medical treatment, in whom acute myocardial infarction had been excluded by serial measurement of creatine kinase and lack of Q waves on ECG. Intervention Coronary angiography and ST segment monitoring for 24 hours. Main outcome measures Concentrations of C reactive protein, troponins T and I, coronary anatomy, presence of transient myocardial ischaemia. Results Median C reactive protein, troponin I, and troponin T concentrations were 17.1u2009mg/dl (4.8 to 203.9), 0.05u2009μg/l (0 to 7.8), and 0.0u2009μg/l (0 to 2.51), respectively. Seven patients (10%) had normal coronaries and 14, 20, and 31 had one, two, or three vessel coronary disease, respectively. Nineteen (26%) had transient myocardial ischaemia, 33 (46%) had complex lesion morphology, and six (8%) had intracoronary thrombus. Of the three markers, troponin T alone was higher in patients with multivessel disease (pu2009<u20090.05) and in those with transient myocardial ischaemia (pu2009<u20090.05), but there was no significant relation between C reactive protein, troponin T or I and lesion morphology or thrombus. Conclusions In patients transferred to a tertiary centre with intractable chest pain, C reactive protein and troponin I are not predictive of transient myocardial ischaemia or lesion morphology, both of which are surrogate markers of outcome. Troponin T is, however, raised in patients with multivessel disease or transient myocardial ischaemia. These serum protein assays cannot be used to stratify the risk of patients with unstable angina who are awaiting transfer to the tertiary centre.

Value of ambulatory ST segment monitoring in patients with chronic stable angina: does measurement of the "total ischaemic burden" assist with management?

OBJECTIVE--To assess the prognostic significance of transient ischaemic episodes during daily activities in patients with stable angina. PATIENTS AND METHODS--172 patients with stable angina attending the cardiac outpatients departments of Hillingdon Hospital (n = 155) and the National Heart Hospital (n = 17) were prospectively studied by exercise testing and 48 hours of ambulatory ST segment monitoring, and followed for prognostic purposes for up to 39 months (mean 24.5 months). Patient inclusion depended on a clinical diagnosis of stable coronary artery disease which necessitated outpatient review (and antianginal treatment in 94% of patients). It was not dependent on objective evidence of reversible ischaemia. Events recorded during the follow up period included death, non-fatal myocardial infarction, unstable angina, and the requirement for revascularisation. RESULTS--72 patients (42%) had transient ischaemic episodes during daily activities, and 104 patients (60.5%) had an ischaemic response to exercise. 63 patients (36%) had evidence of ischaemia on both investigations; with 59 (34%) having no documented ischaemia on either investigation. There were 27 patient events (15.7%) recorded over a mean 24.5 month follow up, including five deaths (2.9%) (three cardiac related (1.7%)), six non-fatal myocardial infarctions (3.5%), six admissions with unstable angina (3.5%), and 10 revascularisation procedures (5.8%). Of the nine hard or objective end points (cardiac death and non-fatal myocardial infarction), only two had evidence of transient ischaemia on ambulatory ST segment monitoring at initial investigation, with 10 of the 25 patients (38.5%) with any cardiac event having such episodes. CONCLUSIONS--The outcome in patients with chronic stable angina receiving standard medical treatment was good over a mean two year follow up period. For the purpose of assessing prognosis over this time scale, there was no advantage to performing ambulatory ST segment monitoring in such patients.

Silent myocardial ischaemia in patients referred for coronary bypass surgery because of angina: a comparison with patients whose symptoms were well controlled on medical treatment.

The frequency and characteristics of silent ischaemia were prospectively studied in 114 patients with confirmed coronary artery disease and angina. Fifty seven patients who had angina that was not adequately controlled by standard medications were referred for elective coronary artery bypass surgery (group 1). Fifty seven other patients had symptoms that were well controlled on medical treatment (group 2). Patients underwent treadmill exercise testing (n = 109) and 48 hours of ambulatory ST segment monitoring (total 5125 hours). Patients in group 1 had more severe coronary artery disease and a shorter time to 1 mm ST segment depression and maximal exercise. Twenty two patients in group 1 (38%) and 16 in group 2 (28%) had greater than or equal to 1 episode of silent ischaemia during 48 hours of ST monitoring. There was no significant difference in the mean frequency of silent ischaemic episodes in 24 hours between the two groups (group 1 0.72 v group 2 0.64); however, the mean frequency of painful ischaemic episodes in 24 hours was greater in group 1 patients (0.51) than in group 2 (0.11). In both groups the frequency of silent ischaemia was significantly related to a positive exercise test, as was the total duration of silent ischaemia. The circadian variation of silent ischaemia showed a peak of episodes in the evening in both groups. The frequency of silent ischaemia in patients with coronary artery disease and angina receiving standard antianginal medications was not related to the severity of symptoms, but was significantly related to a positive exercise test. Thirty three percent of the patients studied had evidence of silent ischaemia during 48 hours of ambulatory ST segment monitoring; however, only four patients (3.5%) had frequent (>/=5) daily episodes of silent ischaemia.

Natural variability of transient myocardial ischaemia during daily life: an obstacle when assessing efficacy of anti-ischaemic agents?

OBJECTIVE: To assess the degree of variability of transient myocardial ischaemia during daily life in patients with coronary artery disease, which could confound the interpretation of trials of the therapeutic effects of anti-ischaemic agents. DESIGN: Prospective method evaluation. SETTING: Tertiary referral centre, outpatient clinic. PATIENTS: Patients with stable angina, confirmed coronary artery disease, and a positive treadmill exercise test for ischaemia. Patients were not preselected on the basis of prior documented transient ischaemia during ambulatory ST segment monitoring. INTERVENTIONS: A simulated drug-study with 4 monitoring phases in 16 subjects. To minimise variability in ischaemic activity, patients underwent weekly 48 hour ambulatory ST segment monitoring outside hospital off all prophylactic therapy on the same weekdays for 4 weeks. MAIN OUTCOME MEASURE: Variability in the frequency and duration of transient myocardial ischaemia. RESULTS: There was marked variability in both ischaemic activity and mean duration of ischaemia in patients with confirmed ischaemia, the greatest degree of variability being between patients and from day to day within weeks within patients, with a further contribution to variability being noted between fortnights within patients. CONCLUSIONS: Despite assessment off all therapy and an adequate period of monitoring (48 hours) with small intervals between monitoring periods (5 days), marked variability in ischaemic activity was noted, and regression towards the mean was clearly shown. Ambulatory ST segment monitoring outside hospital is not a reliable method for assessing the therapeutic effects of anti-ischaemic agents.

CREST-2: Identifying the Best Method of Stroke Prevention for Carotid Artery Stenosis: National Institute of Neurological Disorders and Stroke Organizational Update

One of the great achievements of modern medicine is the successful prevention of stroke and other cardiovascular diseases. Although the incidence of stroke has substantially declined over the last 30 years, ≈200 000 preventable stroke deaths still occur annually in the United States. According to a recent study based on the Greater Cincinnati/Northern Kentucky Stroke Study, annually ≈41 000 strokes in the United States are attributed to extracranial internal carotid artery stenosis. Early revascularization for symptomatic carotid stenosis—that is, in patients with recent ipsilateral stroke or TIA—is well established as effective at preventing ipsilateral stroke. Carotid stenosis in the absence of symptoms is extremely common, but the best treatment is unclear. While 2 randomized trials showed a benefit of carotid endarterectomy (CEA) over antiplatelet therapy with aspirin, the number needed to treat approaches 200. Does aggressive risk factor control change that balance? Population screening for carotid stenosis followed by revascularization is considered to cause net harm. Are complication rates from endarterectomy and stenting now low enough to justify expanding their indications in asymptomatic patients? The National Institute of Neurological Disorders and Stroke (NINDS)–funded CREST-2 trial (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) is an ambitious attempt to further refine the treatment of asymptomatic carotid stenosis.nnAs one of the largest randomized stroke prevention trials, the first CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) was designed to compare the safety and efficacy of 2 stroke prevention procedures for carotid artery narrowing—CEA and carotid artery stenting (CAS)—in symptomatic and asymptomatic individuals. Starting in December 2000, this NINDS-funded trial enrolled >2500 patients at 117 sites in the United States and Canada. Because of slow enrollment, the trial took 9 years to complete. In 2010, the results of CREST indicated that the 2 revascularization procedures were equivalent for …